Elsevier

Leukemia Research

Volume 29, Issue 4, April 2005, Pages 397-400
Leukemia Research

Imatinib mesylate in the treatment of Core Binding Factor leukemias with KIT mutations: A report of three cases

https://doi.org/10.1016/j.leukres.2004.10.005Get rights and content

Abstract

Aim of this study is to investigate the capability of Imatinib to induce an anti-leukemic effect in Core Binding Factor (CBF)-leukemia patients presenting either with extracellular juxtamembrane or kinase KIT mutations. On the basis of a screening analysis for KIT mutations, two patients with a kinase mutation and one with extracellular juxtamembrane mutation, in first or subsequent leukemic relapse, received 400 mg Imatinib twice daily for 30 days. After Imatinib discontinuation, bone marrow cells were re-tested to assess the KIT mutational status and the chromosomal set. In our experience, none of the treated patients had a response by standard criteria; in particular, we did not observe any activity against acute myeloid leukemia (AML) associated with KIT kinase mutations. However, in the patient with extracellular juxtamembrane mutation, Imatinib seems to have some clinical beneficial effect and, most important, is able to abrogate the leukemic subclone carrying the mutation. Whether Imatinib, in combination with other agents, may play a role in the treatment of AML with more sensitive extracellular juxtamembrane KIT mutation remains to be determined.

Introduction

It has been recently documented that the incidence of KIT point mutations ranges from 5% to 40% of newly diagnosed acute myeloid leukemias (AML) with t(8;21) (q22;q22) and inv(16) (p13;q22) [1], [2]. Mutations may affect either the juxtamembrane domain proposed to regulate the activity of an otherwise normal enzymatic site of the KIT receptor, such as insertion or deletions of exon 8 or 11 of the KIT gene, or may affect the structure of the tyrosine kinase domains I and II (kinase domain mutations) as in cases with single amino acid substitution at codon 816 (D816 mutants). These types of mutations lead to a gain-of-function of the KIT receptor and induce a KIT-dependent proliferation. Recently, investigators at the Columbia University reported that Imatinib is able to inhibit KIT-dependent phosphorylation in a human mast cell leukemia cell line subclone (HMC1.1), which expresses only the Val560Gly juxtamembrane mutation, but failed to suppress constitutive phosphorylation of KIT in the HMC1.2 subclone, which expresses both the Val560Gly and kinase mutations (Asp816Val), establishing a general rule whereby classification of mutations may be useful in predicting tumour sensitivity to inhibitory drugs [3].

Aim of the present study is to investigate the capability of Imatinib to induce an anti-leukemic effect in Core Binding Factor (CBF)-leukemia patients presenting either with extracellular juxtamembrane or kinase KIT mutations.

Section snippets

Mutational analysis

Exon 17 mutations in the KIT gene were identified by sequencing and by more sensitive assays as HinfI assay for Asp816Val as previously described [1] and amplification refractory mutation system (ARMS) PCR for Asp816Tyr. Briefly, 168 bp (mutated) ARMS PCR products of KIT exon 17 were generated using the following primers: 17A 5′-AGTTTTCACTCTTTACAAG-3′ and 17B 5′-TTAGAATCATTCTTGATGTA-3′. Denaturing, annealing and extension steps were performed at 94 °C for 30 s, 48 °C for 20 s, 72 °C for 20 s, and a

Patients with KIT kinase mutations

Case no. 1: A 58-year-old woman, with a history of breast cancer, was diagnosed with AML(M4Eo) and D816V KIT mutation on June 2003. After a standard induction chemotherapy (idarubicin and cytarabine), she received two consolidation courses (idarubicin and High Dose-cytarabine; High Dose-cytarabine) but relapsed 3 months thereafter. Treatment with Imatinib was started 8 days after a single dose of cytarabine 100 mg/m2 as continuous infusion and 24 h after hydroxiurea 1500 mg per day orally for 3

Discussion

Complete remission achieved upon administration of Imatinib in the treatment of patients with advanced leukemias has been rarely reported in the recent literature; furthermore, the biological basis of the observed responses remained unknown [5], [6], [7]. Aim of this work was to investigate the capability of Imatinib to induce an anti-leukemic effect in CBF-leukemia patients presenting either with kinase or extracellular juxtamembrane KIT mutations to validate, in vivo, the general paradigm

Acknowledgements

R. Cairoli contributed to the concept and design, interpreted and analyzed the data and provided drafting of the article. A. Beghini contributed to the concept, interpreted and analyzed the data and provided drafting of the article. G. Grillo collected and assembled the data. E. Morello and M. Montillo provided study materials/patients. L. Larizza and E. Morra provided critical revisions and important intellectual content and gave final approval of article.

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